Human tyrosinase-related protein-1 (TYRP1), also known as gp75, (WO 91/14775) (SEQ ID NO: 28) is a melanosomal membrane glycoprotein involved in melanin biosynthesis. It is found predominantly within the melanosomes of melanocytes and is also found expressed on the cell surface of melanocytes and human melanomas.
The TYRP1 antigen is highly immunogenic. Antibodies and T-cells to TYRP1 have been identified in melanoma patients. It appears that both cellular and humoral responses are effective in eliminating melanoma in vivo. Adoptive transfer of melanoma reactive T-cells also results in tumor regression. Antibody response induced by TYRP1 vaccine also could inhibit melanoma growth and metastasis in animals.
Although a variety treatment options for melanoma have been studied including, small molecule inhibitors, chemotherapeutics, immunotherapies including vaccines (for example U.S. Pat. No. 6,168,946), gene therapy/immunostimulants, and anti-angiogenics, at the present time, there are no effective therapies for patients with melanoma. Development of new treatments for this unmet medical need is highly warranted.
Animal studies have resulted in the discovery of the antibody TA99. TA99 (IgG2a), a murine monoclonal antibody (MAb) specific for human and murine TYRP1, localizes to subcutaneous human melanoma in vivo. See Welt et al., Proc. Natl. Acad. Sci. USA 84: 4200-4204 (1987) and U.S. Pat. No. 4,798,790. TA99 treatment inhibited tumor growth and metastasis in mice. See Takechi et al., Clin Cancer Res. 2:1837-42 (1996).
Mice treated with TA99 often lose hair color (depigmentation), suggesting destruction of melanocyte in the skin. The Fc receptor-mediated effector activation appears to play a critical role in the elimination of cells targeted by TA99. The anti-tumor effect of TA99 was dramatically reduced in FcR knockout mice. See Clynes et al., Proc. Natl. Acad. Sci. USA 95:652-656 (1998). However, the murine nature of TA99 means it would be precluded from use as a therapeutic in humans due to potential issues of immunogenicity and further its ability to activate downstream immune effector functions would be limited.
Thus there is a need to provide alternative anti-TYRP1 antibodies which are effective in the treatment of melanoma. The present invention provides alternative anti-TYRP1 antibodies that are effective in the treatment of melanoma.
Additionally, there is a need to provide alternative anti-TYRP1 antibodies which have improved binding affinity for TYRP1 compared with those antibodies known in the art. The present invention provides alternative anti-TYRP1 antibodies which have improved binding affinity for TYRP1 compared with those antibodies known in the art.
Further, there is a need to provide alternative anti-TYRP1 antibodies which have reduced immunogenicity in humans and improved ability to activate downstream immune effector functions such as antibody dependent cellular cytotoxicity (ADCC). The present invention provides chimeric and human anti-TYRP1 antibodies which have reduced immunogenicity in humans and an improved ability to activate downstream immune effector functions such as antibody dependent cellular cytotoxicity (ADCC) compared with those antibodies known in the art.
There also remains a need to provide alternative anti-TYRP1 antibodies which have improved stability via a reduction in protein misfolding and incorrect processing. Preferred antibodies of the present invention have improved stability via reduced protein misfolding and incorrect processing.